Details

Autor(en) / Beteiligte

• Papathomas, Thomas G
• Oudijk, Lindsey
• Persu, Alexandre
• Gill, Anthony J
• van Nederveen, Francien
• Tischler, Arthur S
• Tissier, Frédérique
• Volante, Marco
• Matias-Guiu, Xavier
• Smid, Marcel
• Favier, Judith
• Rapizzi, Elena
• Libe, Rosella
• Currás-Freixes, Maria
• Aydin, Selda
• Huynh, Thanh
• Lichtenauer, Urs
• van Berkel, Anouk
• Canu, Letizia
• Domingues, Rita
• Clifton-Bligh, Roderick J
• Bialas, Magdalena
• Vikkula, Miikka
• Baretton, Gustavo
• Papotti, Mauro
• Nesi, Gabriella
• Badoual, Cécile
• Pacak, Karel
• Eisenhofer, Graeme
• Timmers, Henri J
• Beuschlein, Felix
• Bertherat, Jérôme
• Mannelli, Massimo
• Robledo, Mercedes
• Gimenez-Roqueplo, Anne-Paule
• Dinjens, Winand Nm
• Korpershoek, Esther
• de Krijger, Ronald R

Titel

SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T)

Ist Teil von

• Modern pathology, 2015-06, Vol.28 (6), p.807-821

Ort / Verlag

United States: Elsevier Limited

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• Despite the established role of SDHB/SDHA immunohistochemistry as a valuable tool to identify patients at risk for familial succinate dehydrogenase-related pheochromocytoma/paraganglioma syndromes, the reproducibility of the assessment methods has not as yet been determined. The aim of this study was to investigate interobserver variability among seven expert endocrine pathologists using a web-based virtual microscopy approach in a large multicenter pheochromocytoma/paraganglioma cohort (n=351): (1) 73 SDH mutated, (2) 105 non-SDH mutated, (3) 128 samples without identified SDH-x mutations, and (4) 45 with incomplete SDH molecular genetic analysis. Substantial agreement among all the reviewers was observed either with a two-tiered classification (SDHB κ=0.7338; SDHA κ=0.6707) or a three-tiered classification approach (SDHB κ=0.6543; SDHA κ=0.7516). Consensus was achieved in 315 cases (89.74%) for SDHB immunohistochemistry and in 348 cases (99.15%) for SDHA immunohistochemistry. Among the concordant cases, 62 of 69 (~90%) SDHB-/C-/D-/AF2-mutated cases displayed SDHB immunonegativity and SDHA immunopositivity, 3 of 4 (75%) with SDHA mutations showed loss of SDHA/SDHB protein expression, whereas 98 of 105 (93%) non-SDH-x-mutated counterparts demonstrated retention of SDHA/SDHB protein expression. Two SDHD-mutated extra-adrenal paragangliomas were scored as SDHB immunopositive, whereas 9 of 128 (7%) tumors without identified SDH-x mutations, 6 of 37 (~16%) VHL-mutated, as well as 1 of 21 (~5%) NF1-mutated tumors were evaluated as SDHB immunonegative. Although 14 out of those 16 SDHB-immunonegative cases were nonmetastatic, an overall significant correlation between SDHB immunonegativity and malignancy was observed (P=0.00019). We conclude that SDHB/SDHA immunohistochemistry is a reliable tool to identify patients with SDH-x mutations with an additional value in the assessment of genetic variants of unknown significance. If SDH molecular genetic analysis fails to detect a mutation in SDHB-immunonegative tumor, SDHC promoter methylation and/or VHL/NF1 testing with the use of targeted next-generation sequencing is advisable.